1, 4a-dimethyl-6-hydroxy-7-isopropyl-1, 2, 3, 4, 4a, 9, 10, 10a-octahydrophenanthrene -1-carbonitrile and derivatives thereof



1,4a DIMETHYL 6 HYDROXY 7 ISOPRO- PYL 1,2,3,4,4a,9,10,10a OCTAROPHENAN-THRENE 1 CARBONITRRE AND DERIVA- TEVES THEREOF Wiilard M. Hoehn,Wilmette, 11L, assignor to G. D. Searle 8; Co., Chicago, IIL, acorporation of Delaware No Drawing. Application April 9, 12956 SerialNo. 576,781

7 Claims. (Cl. 260-464) 15 The present invention deals with phenanthrenecarbonitriles, and is specifically concerned with 1,4a-dimethyl- 6hydroxy 7 isopropyl1,2,3,4,4a,9,l0,IOa-octahydrophenanthrene-l-carbonitrile, with ethersand esters thereof, and with methods for their manufacture. Thecompounds of this invention can be represented by the structural formulaOR C 3 I sC CN wherein R can be hydrogen, a lower alkyl radical, or alower alkanoyl radical.

The term R in the foregoing structural formula can represent such loweralkyl radicals as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl,octyl, and branchedchain isomers thereof. It can also represent suchlower alkanoyl radicals as formyl, acetyl, propionyl, butyryl, 4Ovaleryl, hexanoyl, heptanoyl, octanoyl, and their branchedchain isomers,the foregoing alkanoyl radicals being the acyl radicals of alkanoicacids having fewer than 9 carbon atoms.

A satisfactory starting material for the manufacture of the compounds ofthis invention is the dehydrogenated rosin nitrile prepared by reactingdehydrogenated rosin with ammonia at an elevated temperature andremoving the water from the reaction mixture as it is formed, forexample according to the processes disclosed in U. S. 2,534,297 toPutnam. The product obtained from dehydrogenated rosin by the methods ofthe aforementioned patent is crude dehydroabietonitrile, which can becrystallized to give purified dehydroabietonitrile, or 1,4adimethyl 7isopropyl- 1,2,3,4,4a,9,10,lOa-octahydrophenanthrene-l-carbonitrile, asdisclosed therein.

1,4a dimethyl 7-isopropyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene lcarbonitrile (dehydroabietonitrile) undergoes Friedel-Crafts reactionswith acyl halides to yield 6-acyl substitution products. For example,the aluminum chloride-catalyzed reaction of 1,4a-dimethyl-7- isopropyl1,2,3,4,4a,9,10,10a octahydrophenanthrene-lcarbonitrile with acetylchloride alfords 1,4a-dimethyl-6- acetyl 7isopropyl-l,2,3,4,4a,9,10,10a-octahydrophenanthrene-l-carbonitrile. Byreaction of this compound, suitably in a hydrocarbon or a chlorinatedhydrocarbon solvent, with a peroxy acid such as performic acid,peracetic acid, perbenzoic acid, perphthalic acid, orper0xytrifiuoroacetic acid, there occurs oxidative rupture of acarboncarbon bond and the formation of 1,4a-dimethyl-6-acetoxy 7isopropyl l,2,3,4,4a,9,10,10a-octahydropl1enanthrene-l-carbonitrile.This compound can be isolated 2,316,907 Patented Dec. 17, 1957 directlyfrom the reaction mixture. However, a method of operation which isslightly more satisfactory involves subjecting the crude reactionproduct to a basic hydrolysis, whereby the acetoxy group is hydrolyzed.Acidification then generates the free phenol, 1,4a-dimethyl-6- hydroxy 7-isopropyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-l-carbonitrile,which is readily separated and purified. Other 6-acyl substitutionproducts of dehydroabietonitrile are also suitable for use in theprocesses of this invention. For example, the aluminum chloridecatalyzedreaction of dehydroabietonitrile with butyryl chloride yields1,4a-dimethyl-6-butyryl-7-isopropyl-1,2,3,4,4a-9,10,10a-octahydrophenanthrene-l-carbonitrile. This lattercompound, upon treatment with a peroxy acid followed by hydrolysis ofthe primary reaction product, yields the samel,4a-dimethyl-6-hydroxy-7-isopropyl-1,2,3, 4,4a,9,10,10aoctahydrophenanthrene-l-carbonitrile that is obtained from thecorresponding 6-acetyl derivative.

Lower alkanoic acid esters of this invention can be prepared,alternatively, by subjecting a 6-alkanoyl substitution product ofdehydroabietonitrile to oxidation with a peroxy acid and isolating thereaction product without an intervening hydrolytic operation, or bysubjecting 1,4adimethyl 6 hydroxy 7 isopropyl 1,2,3,4,4a,9,10,l0aoctahydrophenanthrene-l-carbonitrile to reaction with an acylating agentsuch as a lower alkanoic acid anhydride or a lower alkanoyl halide,suitably in pyridine as a solvent. Lower alkyl ethers of this inventioncan be prepared by treatment of1,4a-dimethyl-6-hydroxy-7-isopropyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrenel carbonitrile with a basic reagent and an alkylating agent such as adialkyl sulfate or an alkyl halide. Becuse of the relative unreactivityof the sterically-hindered nitrile group in these compounds, suchreactions can be conducted in basic media without effecting substantialhydrolysis of the nitrile group.

The compounds of the present invention have valuable pharmacologicalproperties. They exhibit hormonal effects and, specifically, areandrogenic and anabolic agents. In addition, they exhibit certain of thebiological characteristics which are associated with estrogenichormones, while at the same time they show little or no estrogenicactivity. Thus, the administration of the compounds of this inventioncauses a reduction in the serum ratio of cholesterol to phospholipids,and therefore results in an inhibitory effect on the arterial depositionof cholesterol. Because these compounds achieve this result, which iscommonly associated with estrogen therapy, with out producing acorresponding ferninization, they are useful in the treatment ofhypercholesterolemia and disorders associated therewith.

This invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. in these examples temperaturesare given in degrees centigrade C.), pressures in millimeters (mum) ofmercury and quantities of materials in parts by weight.

Example 1 With efiicient stirring, parts of aluminum chloride is addedto a solution of parts of l,4a-dimethyl-7- isopropyl1,2,3,4,4a-9,l0,lOa-octahydrophenanthrene-lcarbonitrile and 31 parts ofacetyl chloride in 4-25 parts of nitrobenzene maintained at about 5 to+8 C. The reaction mixture is stirred for an additional 3 hours and keptunder refrigeration for 2-3 days. The mixture is then poured on about500 parts of ice, and sufiic1ent ether is added to cause the density ofthe organic phase to become less than the density of the aqueous phase.The organic phase is separated and washed with a total of 600 parts ofwater in two portions, a total of 600 parts of 2% sodium hydroxidesolution in two portions and then with several portions of Wfllfil'. Theethereal solution is dried over sodium sulfate, filtered, andconcentrated on a steam bath and finally by a vacuum distillation atabout 90100 C. and a pressure of 15 mm. in order to remove the ether andnitrobenzene. A solution of the residue in chloroform is treated withactivated charcoal, filtered and diluted with methanol. The precipitatedproduct, l,4a-dimethyl6-acetyl7-isopropyl-1,2,3,4,4a,9,10,10aoctahydrophenanthrene 1- carbonitrile is collected on a filter. Anadditional quantity of this product is obtained by concentration of themother liquor. This compound melts at 156-158" C. and has the followingstructural formula Example 2 To a solution of 10 parts of1,-4a-dimethyl-6-acetyl-7- isopropyl 1,2,3,4,4a-9,10,l0a-octahydrophenanthrene-1- carbonitrile in 90 parts of benzenemaintained at 5-10 C. there is added a 0.3 molar solution of perbenzoicacid in benzene containing a total of 8.4 parts of perbenzoic acid.After 1 hour, the reaction mixture is allowed to warm to about 25 C.,and it is maintained at this temperature in the dark for an additional 3weeks. It is then washed successively and rapidly with 400 parts ofwater, with 600 parts of 3% sodium thiosulfate solution in 2 portions,with 400 parts of 2% sodium hydroxide solution in 2 portions and finallywith several portions of water. The organic phase is concentrated todryness and the oily residue is heated under reflux for 2 minutes with40 parts of methanol and parts of potassium hydroxide. Water (100 parts)is then added, and a small amount of insoluble material is removed byfiltration. The filtrate is acidified and cooled, and the precipitatedproduct is collected on a filter. For purification 9 parts of thiscrude, dried product is dissolved in a mixture of 100 parts ofchloroform and 25 parts of ether; the resulting solution is concentratedto about one-third of its original volume and then diluted with aboutparts of petroleum ether. When separation of the crystalline product iscomplete, it is collected on a filter and Washed with petroleum ether.This compound is 1,4a dimethyl-6-hydroxy-7-isopropyl-1,2,3,4,4a,9,10,lOa-octahydrophenanthrene-l-carbonitrile melting at about 202-203 C. Itshows an ultraviolet absorption maximum at about 282 millimicrons with amolecular extinction coefficient of about 3550. This compound has thestructural formula Example 3 A solution is prepared from 6 parts of1,4a-dimethyl-6- hydroxy 7-isopropyl-l,2,3,4,4a,9,l0,10aoctahydrophenanthrene-l-carbonitrile, 35 parts of methanol, 15 parts ofwater, and 2.6 parts of sodium hydroxide. To this solution, stirred andmaintained at about 60 C. there is added in several portions a total of8.5 parts of dimethyl sulfate. Upon dilution with 150, parts of waterand cooling, an insoluble gummy product separates from solution. This iswashed by decantation with water and then dissolved in ether. Theethereal solution is washed with water, with 2% sodium hydroxidesolution, and finally with several portions of water. The residualproduct obtained by concentration of the ethereal solution is purifiedby distillation. At a pressure of 0.05 mm. there is obtained adistillate, boiling point about 168-170 C., of 1,4adimethyl-6-methoxy-7-isopropyl-1,2,3,4,4a,9,10,10at-octahydrophenanthrene1-carbonitrile. This compound has anultraviolet absorption maximum at about 281 millimicrons with amolecular extinction coefficient of 3600. The structural formula is OCH:CH:

By the substitution of 10.5 parts of diethyl sulfate for the dimethylsulfate in the foregoing procedure, there is obtained1,4a-dimethyl-6-ethoxy-7-isopropyl-l,2,3,4,4a,9,l0,l0a-octahydrophenanthrene-l-carbonitrile.

Example 4 A solution of 3 parts of 1,4aalimethyl-6-hydroxy-7-isopropyll,2,3,4,4a,9,l0,l0a octahydrophenanthrene 1- carbonitrile, parts ofanhydrous propyl alcohol, 1.85 parts of propyl iodide and 0.9 part ofsodium propoxide is heated under reflux for 1 hour. There is then addedan additional 0.68 part of propyl iodide and 0.33 part of sodiumpropoxide, and the mixture is refluxed for 1 more hour. The mixture isthen concentrated by distillation to about one-half its original volumeand poured, with stirring, into 300 parts of Water. The insolubleprecipitate of 1,4a dimethyl 6 propoxy 7 isopropyl l,2,3,4,4a,9,l0,10a-octahydrophenanthrene-l-carbonitrile is collected and washed.This compound shows an ultraviolet absorption maximum at about 281millimicrons. It has the structural formula OCHsCHzOHs H5 CH(CH3):

Example 5 A solution of 10 parts of 1,4a-dimethyl-6-hydroxy-7-isopropyl1,2,3,4,4a,9,10,10a octahydrophenanthrene lcarbonitrile in 20 parts ofpyridine and 40 parts of acetic anhydride is heated at about C. for 1hour. The cooled reaction mixture is slowly diluted with 400 parts ofwater. The mixture is chilled and, when separation of the solid productis complete, it is collected on a filter and washed with Water. Byrecrystallization from aqueous methanol there is obtained purified1,4a-dimethyl-6acetoxy 7 isopropyl 1,2,3,4,4a,9,10,10a octahydrophenan-5 threne-l-carbonitrile melting at about 135-136 C. This compound showsultraviolet absorption maxima at about 268 and 276 Inillimicrons withrespective molecular extinction coeflicients of about 1210 and 1280. Thestructural formula is HIC/ ON Example 6 A solution of parts of1,4a-dimethyl-6-hydroxy-7-isopropyl 1,2,3,4,4a,9,10,10aoctnhydrophenanthrene 1- carbonitrile, 25 parts of pyridine and parts ofbutyric anhydride is heated at about 90-100 C. for 6 hours. The cooledmixture is diluted with several times its volume of Water, and theprecipitated product is collected and washed. This compound is1,4a-dimethyl-6-butyroxy-7- isopropyl 1,2,3,4,4a,9,10,10aoctahydrophenanthrene-lcarbonitrile which shows ultraviolet absorptionmaxima at about 268 and 276 millirnicrons and has a structural formula 0C O CHzCHgCH;

CH(CHI)R What is claimed is: 1. A compound of the structural formula ORCH3 wherein R is a member of the group consisting of hydrogen, loweralkyl radicals, and lower alkanoyl radicals 2. A compound of thestructural formula EC CN 5. 1,4a dimethyl 6 acetoxy 7 isopropyl 1,2,3,4,4a,9,10,10a-octahydrophenanthrene-l-carbonitrile.

6. 1,421 dimethyl 6 hydroxy 7 isopropyl 1,2,3,4,4a,9,10,10a-octahydrophenanthrene-l-carbonitrile. 7. In a process forthe manufacture of a compound of the structural formula 0R CH1 H30 CN'wherein R is a member of the group consisting of hydrogen, lower alkylradicals, and lower alkanoyl radicals, the

steps which comprise treating a solution of 1,4a-dimethyl- 6 acctyl 7isopropyl 1,2,3,4,4a,9,10,10a octahydrophenanthrene-l-carbonitfile witha peroxy acid, subjecting the oxidation product to basic hydrolysis andsubsequent acidification, and isolating 1,4a-dimethyl-6-hydroxyo 7isopropy1-1,2,3,4,4a,9,10,10a-octahydrophenanthrenol-carbonitrile.

References Cited in the file of this patent UNITED STATES PATENTSSanderson June 12, 1956 OTHER REFERENCES Campbell et a1.: Jour. Am.Chem. Soc., vol. 64, pp. 928-35 (1942).

1. A COMPOUND OF THE STRUCTURAL FORMULA